Hypercholesterolemia, particularly an increase in low-density lipoprotein cholesterol (LDL-C) levels, constitutes a major risk for the development of atherosclerosis and coronary heart disease (CHD), the leading cause of death and disability in the Western world. Numerous studies have demonstrated that reducing LDL-C levels, mainly with 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMG CoA) inhibitors (commonly referred to as statins), reduces the risk of CHD, with a strong direct relationship between LDL-C levels and CHD events; for each 1 mmol/L (˜40 mg/dL) reduction in LDL-C, cardiovascular disease (CVD) mortality and morbidity is lowered by 22%. Greater reductions in LDL-C produce greater reduction in events, and comparative data of intensive versus standard statin treatment suggest that the lower the LDL-C level, the greater the benefit in patients at high cardiovascular risk.
The long-term elevations of LDL-C leading to a progressive accumulation of coronary atherosclerosis require a long-term management, which includes lifestyle measures as the primary intervention. However, since lifestyle measures rarely reduce plasma LDL-C by >15%, use of pharmacologic treatments are needed to adequately treat dyslipidemic patients. Current LDL-C lowering medications include statins, ezetimibe (EZE), fibrates, niacin, and bile acid sequestrants, of which statins are the most commonly prescribed, as they have shown a great ability to lower LDL-C and reduce CHD events. Since hypercholesterolemia is largely asymptomatic, side effects of pharmacologic agents used to manage it can undermine patient compliance. In several cohort studies, the reported rate of adherence to statin therapy at 1 year ranged from 26% to 85%, with a rapid decline in adherence rates typically observed within the first few months.
Despite the widespread availability of lipid-modifying therapies, such as statins, approximately 30% of all adult patients treated for hypercholesterolemia in the United States between 1999 and 2006 failed to achieve their recommended LDL-C targets. Reasons for this include poor adherence to therapy, drug-resistance/intolerance, and the positive relationship between adverse event rates and increasing dosage. Moreover, since the most effective lipid-modifying therapies can only reduce LDL-C levels by up to 55%, target attainment rates in patients that require substantial reductions in LDL-C, such as those with familial hypercholesterolemia, are often significantly lower than might be expected. More effective lipid-modifying therapies and treatment regimens are therefore required to improve target attainment rates in these patients.
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a proprotein convertase belonging to the proteinase K subfamily of the secretory subtilase family. Evidence suggests that PCSK9 increases plasma LDL cholesterol by promoting degradation of the LDL receptor, which mediates LDL endocytosis in the liver, the major route of LDL clearance from circulation.
The use of PCSK9 inhibitors (anti-PCSK9 antibodies) to reduce serum total cholesterol, LDL cholesterol, and serum triglycerides has been described in U.S. Pat. Nos. 8,062,640 and 8,357,371, and U.S. Patent Application Publication No. 2013/0064834. However, there remains a need in the art for improved therapeutic methods.